MRI Features in Transthyretin Amyloidosis of the Carpal Tunnel and Amyloid-Negative Control: A Case Report

MRI Features in Transthyretin Amyloidosis of the Carpal Tunnel and Amyloid-Negative Control: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report MRI Features in Transthyretin Amyloidosis of the Carpal Tunnel and Amyloid-Negative Control: A Case Report Jean Pierre Abdallah, Marcus Saldanha, Margherita Leo, Mathieu Boily, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8818347/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Amyloidosis is a systemic disorder characterized by extracellular protein deposition, with transthyretin amyloidosis being the most common subtype. Carpal tunnel syndrome is a frequent early manifestation, yet detailed MRI characterization of amyloid deposition in the wrist remains limited. We present MRI findings from one severe transthyretin amyloidosis case: a 65-year-old male with severe carpal tunnel syndrome secondary to transthyretin amyloidosis wild-type. The subject underwent wrist MRI using T1 and proton density sequences. This case demonstrated extensive flexor tendon thickening, severe tenosynovitis, and hyperintense, striated amyloid deposition within the tenosynovium. MRI revealed distinct patterns of amyloid involvement in carpal tunnel syndrome, highlighting potential imaging biomarkers for characterizing transthyretin amyloidosis and enabling the early detection of cardiac involvement. These findings highlight the potential of MRIs in non-invasive amyloid characterization. As such, larger studies would be required to further validate these observations and integrate MRI into early amyloidosis diagnostic pathways. Amyloidosis Carpal Tunnel Syndrome Transthyretin Amyloid Magnetic Resonance Imaging Magnetization Transfer Ratio Figures Figure 1 Figure 2 Figure 3 Introduction Amyloidosis is a systemic disorder characterized by extracellular deposition of misfolded proteins as insoluble fibrils in various tissues [ 1 , 2 ]. Among its subtypes, transthyretin amyloidosis (ATTR) is a particular case stemming from the misfolding of transthyretin, a transport protein primarily synthesized in the liver, with a prevalence of 16.6 cases per million people [ 3 ]. These insoluble amyloid fibrils progressively infiltrate organ systems and connective tissues, leading to structural disruption and loss of function. Two major subtypes are recognized: hereditary ATTR, which stems from mutations in the TTR gene, and wild-type ATTR (ATTRwt), which is associated with aging [ 1 , 4 ]. Furthermore, ATTRwt is increasingly recognized as a common cause of heart failure in older adults [ 1 ], but early extra-cardiac manifestations, particularly within the musculoskeletal system, are frequently underappreciated [ 6 – 7 ]. Carpal tunnel syndrome (CTS) is one of the earliest and most prevalent peripheral manifestations of ATTR amyloidosis, with studies estimating that approximately 10–15% of patients with CTS have underlying amyloid deposition [ 6 ]. CTS arises from compression of the median nerve within the carpal tunnel and typically presents with pain, numbness, and hand weakness. In the setting of ATTR, amyloid deposits accumulate in the flexor tendons, transverse carpal ligament, and surrounding tenosynovium, leading to tissue hypertrophy and progressive nerve entrapment (Fig. 1 ) [ 7 ]. Indeed, CTS often precedes the diagnosis of systemic ATTR by 4 to 10 years and may serve as an indicator for both ATTRwt and ATTRv [ 7 – 9 ]. Recognition of this relationship is critical, as bilateral CTS in older patients may reflect underlying systemic amyloidosis. While histopathological confirmation through biopsy remains the diagnostic reference standard, it is only performed in patients with severe carpal tunnel syndrome and willing to undergo release surgery. Imaging may play an important role in the non-invasive assessment of amyloid-related CTS. Conventional MRI can detect morphological abnormalities such as tendon thickening and nerve enlargement but lacks specificity for amyloid infiltration. These MRI findings may allow clinicians to identify patients who warrant further diagnostic evaluation using histopathological testing, facilitating diagnosis before cardiac or other organ involvement becomes clinically apparent. In this report, we describe the MRI findings in a 65-year-old male with biopsy-confirmed wild-type ATTR and bilateral CTS. This case shows distinct imaging features of amyloid involvement in the carpal tunnel, including striated hyperintensity within the thickened tenosynovium and flexor tendons. Few studies to date have detailed amyloid-associated alterations in the wrist. As such, this case highlights the diagnostic potential of MRI in identifying early peripheral amyloid involvement and may guide future research aimed at integrating musculoskeletal imaging into the diagnostic pathway for systemic amyloidosis. Case Report A 65-year-old male first presented to the clinic for cardiac evaluation. His past medical history included a remote episode of pericarditis in 2009, without clinical signs of congestive heart failure. Subsequent investigations led to a diagnosis of ATTRwt. At the time of cardiac evaluation, the patient reported persistent mild numbness in the right wrist. He had a history of severe bilateral CTS, more pronounced on the right, characterized by chronic numbness, pain, and sharp tingling sensations. He had previously undergone bilateral carpal tunnel release surgery and histopathological analysis of tenosynovial tissue obtained during the procedure revealed amyloid deposition, which retrospectively confirmed the diagnosis of ATTRwt in 2022. No pre-operative MRI of the wrists was performed prior to the carpal tunnel release procedures. Wrist MRI was performed on April 12, 2024, to further investigate persistent CTS-related symptoms. At the time of evaluation, no pharmacological treatment targeting ATTRwt had been initiated. The protocol included T1-weighted and proton density sequences. Following MRI comparison with a 76 year old amyloid negative patient with moderate-severe CTS, imaging revealed multiple findings consistent with amyloid deposition. There was marked thickening of the flexor tendons bilaterally, with abnormal signal intensity qualified as striated and heterogeneous infiltration. The tenosynovium appeared hyperintense with internal striations and diffuse thickening. The carpal tunnel itself exhibited a cloudy appearance suggestive of fluid accumulation, potentially representing edema. The median nerve was severely compressed, with visible enlargement, nodular thickening, and disrupted fascicular architecture. Moderate-to-severe thickening of the flexor retinaculum was also observed (Fig. 2). Further quantitative analysis demonstrated that the ATTR subject exhibited overall larger tissue structures compared with the amyloid-negative subject (Table 1). Quantitative Features ATTRwt Amyloid Negative CSA of Carpal Tunnel Right: 2.81 | Left: 2.62 Average: 2.72 Right: 1.7 | Left: 1.71 Average: 1.71 Nerve Diameter Right: 0.36 | Left: 0.20 Average: 0.28 Right: 0.20 | Left: 0.14 Average: 0.17 Retinaculum Thickness (cm) Right: 0.21 | Left: 0.23 Average: 0.22 Right: 0.16 | Left: 0.13 Average: 0.15 CSA of All Tendons Right: 1.26 | Left: 1.19 Average: 1.23 Right: 0.96 | Left: 0.96 Average: 0.96 CSA of FDP Right: 0.69 | Left: 0.66 Average: 0.68 Right: 0.44 | Left: 0.42 Average: 0.43 CSA of FDS Right: 0.47 | Left: 0.42 Average: 0.45 Right: 0.32 | Left: 0.32 Average: 0.32 CSA of FPL Right: 0.10 | Left: 0.11 Average: 0.11 Right: 0.20 | Left: 0.22 Average: 0.21 CSA of ECU Right: 0.40 | Left: 0.39 Average: 0.40 Right: 0.14 | Left: 0.16 Average: 0.15 Third Space Thickness Right: 1.19 | Left: 1.23 Average: 1.21 Right: 0.54 | Left: 0.61 Average: 0.58 Quantitative morphometric analysis of wrist structures demonstrating differences in carpal tunnel cross-sectional area, median nerve diameter, and flexor tendon bulk between the right and left sides of ATTRwt and amyloid negative subjects. Measurements included the median nerve, individual flexor tendons, the ECU, and third space thickness. Note: All values in cm² unless otherwise specified. CSA: Cross-sectional area; MN: Median nerve; FDP: Flexor digitorum profundus; FDS: Flexor digitorum superficialis; FPL: Flexor pollicis longus; ECU: Extensor carpi ulnaris; TSVM: Tenosynovium. Values represent the average of each patient's right and left wrists. Table 1. Quantitative Morphometric Analysis of Wrist Structures in ATTRwt compared with an Amyloid-Negative Control. Cross-sectional areas (CSA), nerve diameter, and other structural measurements in ATTRwt compared with an Amyloid-Negative Control. Moreover, severe tendinosis of the extensor carpi ulnaris and mild-to-moderate erosive changes of the carpal bones were observed in the ATTR subject, compared with only mild findings in the amyloid-negative subject (Table 2). Qualitative Features ATTRwt Amyloid Negative Tenosynovium Thickness Severe Mild Retinaculum Thickness Moderate-to-Severe Mild ECU Tendinosis Severe Mild-to-Moderate Carpal Bone Erosion Mild-to-Moderate Mild Note: ECU: Extensor carpi ulnaris; MTR: Magnetization Transfer Ratio; Severe: Marked structural or pathological changes that are clearly abnormal and likely to impact function; Moderate: Noticeable alterations that may contribute to dysfunction but are not as severe or widespread; Mild: Minimal changes that are present but unlikely to have a significant functional impact. Table 2. Qualitative MRI Features of the Wrist in ATTRwt and an Amyloid-Negative Control. Subjective grading of tenosynovium thickness, retinaculum thickness, tendinosis, and bone erosion in ATTRwt and an amyloid negative control. Corresponding magnetization transfer ratio (MTR) imaging confirmed these findings, demonstrating globally elevated ratios within the tenosynovium, flexor tendons, and median nerve compared with the amyloid-negative subject (Fig. 3). These elevations, consistent with the T1 and PD observations, suggest increased macromolecular density in the affected tissues. Discussion This case supports a growing body of evidence suggesting that MRI can serve as a valuable noninvasive tool in the assessment of amyloid-related CTS. While CTS is a common condition in the general population, its association with ATTR, is increasingly recognized as a potential early clinical manifestation. In this patient, detailed wrist MRI revealed characteristic features of amyloid infiltration, including thickened flexor tendons with striated signal changes, hyperintense tenosynovium, and severe median nerve compression, findings that align with previously reported imaging patterns of amyloid deposition. These observations underscore the utility of MRI not only for symptom evaluation but also for identifying musculoskeletal involvement in systemic amyloidosis, potentially aiding in earlier diagnosis. While there are publications describing MRI findings in amyloidosis, there is currently no published literature describing MRI evaluation of specifically ATTR amyloidosis in the wrist. A study describing β2-microglobulin amyloid deposition in the wrist [ 10 ] demonstrates imaging findings with similarities to those observed in this case. However, this area remains significantly under-researched. This gap in the literature further strengthens the rationale for the present case study, which aims to demonstrate the potential role of MRI as a non-invasive tool to promote further investigation of ATTR amyloidosis.to promote further investigation of ATTR amyloidosis. While tenosynovial biopsy remains the reference standard for confirming amyloid deposition, it is typically reserved for more severe cases and performed at the surgeon’s discretion. As a result, many patients with mild to moderate symptoms of CTS may not undergo tissue sampling or any MRI imaging, leading to missed opportunities for early diagnosis of systemic amyloidosis. In carpal tunnel patients with clinical suspicion or risk factors for amyloidosis, non-invasive wrist MRI may offer an opportunity to identify imaging features suggestive of amyloid involvement, thereby prompting targeted referral for further amyloid-specific evaluation without immediate need for invasive testing. In carpal tunnel patients with clinical suspicion or risk factors for amyloidosis, non-invasive wrist MRI may offer an opportunity to identify imaging features suggestive of amyloid involvement, thereby prompting targeted referral for further amyloid-specific evaluation without immediate need for invasive testing. Importantly, the distinct MRI findings observed in this case highlight the potential role of imaging in recognizing amyloid involvement in patients presenting with CTS who have not yet been evaluated for systemic disease. These underutilized radiologic markers, such as striated tendon signal changes, tenosynovial thickening, and nerve compression and fascicular distortion, may serve as early indicators of transthyretin amyloidosis, even in the absence of overt cardiac symptoms. In clinical practice, MRI could support decision-making around whether to pursue biopsy during carpal tunnel release surgery, helping to identify amyloid earlier and guide appropriate referral for systemic evaluation. For qualitative assessment, a three-tier severity grading system was applied based on expert radiologic interpretation of tissue thickening and structural alteration (Table 2). This grading scale categorizes findings as severe, reflecting marked structural or pathological changes likely to impact function; moderate, indicating noticeable alterations that may contribute to dysfunction but are not extensive; and mild, representing minimal changes unlikely to have significant functional impact. This framework was used to standardize descriptive interpretation of imaging findings in the absence of established quantitative thresholds and serves as an exploratory approach pending future validation. Given the availability of disease-modifying therapies for ATTRwt, early identification is essential to improving patient outcomes. Although this report is limited to a single case, it highlights an imaging phenotype that warrants further investigation to determine whether specific MRI patterns can reliably suggest the presence of ATTRwt. While standard MRI can detect features such as tendon thickening, tenosynovial changes, and median nerve enlargement which may be found in other systemic disorders, the extent of thickening in addition to the integration of advanced techniques, such as MTR imaging and T1rho mapping may enhance the ability to quantify amyloid burden and differentiate ATTR-related changes from more common causes of CTS. MTR imaging assesses macromolecular content within tissue; in the context of amyloidosis, elevated MTR values may reflect increased amyloid fibril deposition, offering a noninvasive surrogate marker of disease burden [ 11 ]. Comparative and quantitative imaging approaches may help refine diagnostic criteria, offering noninvasive alternatives to tissue biopsy. T1rho mapping could help assess cartilage integrity, aiding in the understanding of amyloid infiltration processes [ 12 ]. These technical refinements not only improve diagnostic confidence but also hold promise for future use in monitoring disease progression and therapeutic response; further investigation is currently underway to better define their clinical applicability. In summary, this case demonstrates the potential of MRI to detect musculoskeletal involvement in ATTRwt amyloidosis and underscores its role in identifying amyloid-related CTS. These findings support the need for further research into integrating advanced musculoskeletal MRI into the diagnostic algorithm for transthyretin amyloidosis, highlighting its potential role in early detection prior to overt cardiac involvement and in guiding clinical decision-making. Patient Perspective The patient reflected that receiving the diagnosis of systemic amyloidosis was a difficult experience for both himself and his family. Learning of the condition at 65 years of age added to the emotional weight of the diagnosis. The carpal tunnel release surgery provided meaningful symptomatic relief; however, he mentioned the improvement was temporary, as loss of mobility and intermittent pain persisted due to the severity of amyloid already present. Still, he expressed appreciation for the MRI evaluation and this study, noting that it offered a clear window into what was truly occurring within his wrists. Additionally, the imaging findings were reviewed with radiologists and physicians, who indicated that this level of detailed characterization in the early stages of disease may help enable monitoring in patients who are often undetected, particularly those with mild to moderate carpal tunnel symptoms. He also shared that learning about this research brought him comfort, knowing that a non-invasive early detection method could help others like him whose lives are fundamentally changed by the disease. He emphasized that identifying amyloidosis earlier could enable treatments to alter the disease course, and that this possibility gave him genuine hope for future patients. Declarations Author Contribution: All authors were involved in the case and preparation of the manuscript and/or imaging. Ethics approval: The protocol was approved by McGill University Health Center Research Ethics Board - Centre for Applied Ethics in accordance with the International Council for Harmonisation Guideline E6 (Revision 3) on Good Clinical Practice and the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2022). Consent to Participate: Informed consent was obtained from the patient for participation in this study. Consent to Publish: Informed consent was obtained from the patient for publication. Conflict of interest: The authors declare no conflict of interests. Data Availability: Qualitative MRI features of the wrist are documented in Table 2. This dataset includes descriptive features observed in MRI scans, offering insights into the qualitative aspects of wrist imaging. Quantitative morphometric analysis of wrist structures is available in Table 1. This dataset provides detailed measurements and analysis of various wrist structures, contributing to the understanding of wrist morphology. The data that supports the findings of this study are available from the corresponding author upon reasonable request. Acknowledgments Jean-Pierre Abdallah served as the primary author of the manuscript. Marcus Saldanha contributed as a co-author, was responsible for patient recruitment, performed the MRI scans, and provided assistance in manuscript preparation. The authors gratefully acknowledge the support of the McGill University Health Centre, particularly the Department of Radiology, and Dr. Mathieu Boily (MSK Radiologist) for his guidance. We also thank the Courtois Cardiovascular Signature Program and the Courtois CMR Research Group for access to the GE MRI system, as well as MRI technologist Maggie Leo for her expertise and assistance with image acquisition. We sincerely thank the patient who participated in this study for their time and cooperation. The authors are also grateful to Dr. Michael Chetrit, Dr. Mathieu Boily, and Dr. Javad Raffee for their valuable input and support throughout the course of this project. References Ash S, Shorer E, Ramgobin D, Vo M, Gibbons J, Golamari R, et al. Cardiac amyloidosis - A review of current literature for the practicing physician. Clin Cardiol. 2021;44(3):322–31. https://doi.org/10.1002/clc.23572 . Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872–91. https://doi.org/10.1016/j.jacc.2019.04.003 . Laires PA, Li X, Uday AM, Quarta CC, Silva AM. Prevalence and incidence of amyloid transthyretin amyloidosis in the USA: insights from claims databases and electronic health records. Open Heart. 2025;12:e003781. https://doi.org/10.1136/openhrt-2025-003781 . Irabor B, McMillan JM, Fine NM. Assessment and Management of Older Patients With Transthyretin Amyloidosis Cardiomyopathy: Geriatric Cardiology, Frailty Assessment and Beyond. Front Cardiovasc Med. 2022;9:863179. https://doi.org/10.3389/fcvm.2022.863179 . Cuddy SAM, Falk RH. Amyloidosis as a Systemic Disease in Context. Can J Cardiol. 2020;36(3):396–407. https://doi.org/10.1016/j.cjca.2019.12.033 . Saldanha M, Chen LK, Solomon J, Cunanan K, Tournoux F, Massie R, et al. Beyond the Heart: Exploring Extracardiac Manifestations in Cardiac Amyloidosis for Early Diagnosis. Curr Cardiol Rep. 2025;27(1):105. https://doi.org/10.1007/s11886-025-02251-6 . Donnelly JP, Hanna M, Sperry BW, Seitz WH Jr. Carpal Tunnel Syndrome: A Potential Early, Red-Flag Sign of Amyloidosis. J Hand Surg Am. 2019;44(10):868–76. https://doi.org/10.1016/j.jhsa.2019.06.016 . Sperry BW, Reyes BA, Ikram A, Donnelly JP, Phelan D, Jaber WA, et al. Tenosynovial and Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release. J Am Coll Cardiol. 2018;72(17):2040–50. https://doi.org/10.1016/j.jacc.2018.07.092 . Zegri-Reiriz I, de Haro-Del Moral FJ, Dominguez F, Salas C, de la Cuadra P, Plaza A, et al. Prevalence of Cardiac Amyloidosis in Patients with Carpal Tunnel Syndrome. J Cardiovasc Transl Res. 2019;12(6):507–13. https://doi.org/10.1007/s12265-019-09895-0 . Kiss E, et al. Dialysis-related amyloidosis revisited. AJR Am J Roentgenol. 2005;185(6):1460–7. https://doi.org/10.2214/AJR.04.1309 . Kollmer J, Hegenbart U, Kimmich C, Hund E, Purrucker JC, Hayes JM, et al. Magnetization transfer ratio quantifies polyneuropathy in hereditary transthyretin amyloidosis. Ann Clin Transl Neurol. 2020;7(5):799–807. https://doi.org/10.1002/acn3.51049 . Kotecha T, Martinez-Naharro A, Treibel TA, Francis R, Nordin S, Abdel-Gadir A, et al. Myocardial Edema and Prognosis in Amyloidosis. J Am Coll Cardiol. 2018;71(25):2919–31. https://doi.org/10.1016/j.jacc.2018.03.536 . Additional Declarations No competing interests reported. Supplementary Files CAREChecklistEnglish2013.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 13 Apr, 2026 Reviews received at journal 23 Mar, 2026 Reviewers agreed at journal 22 Mar, 2026 Reviewers agreed at journal 16 Mar, 2026 Reviews received at journal 09 Mar, 2026 Reviewers agreed at journal 27 Feb, 2026 Reviewers invited by journal 25 Feb, 2026 Editor assigned by journal 18 Feb, 2026 Submission checks completed at journal 17 Feb, 2026 First submitted to journal 17 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8818347","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":597148027,"identity":"6e435c81-2ebd-4411-9520-e7c1c9b55ac1","order_by":0,"name":"Jean Pierre Abdallah","email":"data:image/png;base64,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","orcid":"","institution":"American University of Beirut","correspondingAuthor":true,"prefix":"","firstName":"Jean","middleName":"Pierre","lastName":"Abdallah","suffix":""},{"id":597148028,"identity":"ac20bda7-a439-49c2-b548-53876cd788af","order_by":1,"name":"Marcus Saldanha","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"Marcus","middleName":"","lastName":"Saldanha","suffix":""},{"id":597148029,"identity":"146a1789-65a8-4436-8b9c-72c01fdabe87","order_by":2,"name":"Margherita Leo","email":"","orcid":"","institution":"McGill University Health Centre","correspondingAuthor":false,"prefix":"","firstName":"Margherita","middleName":"","lastName":"Leo","suffix":""},{"id":597148030,"identity":"ccdd1298-810f-4906-af17-3d84fe0d1a6d","order_by":3,"name":"Mathieu Boily","email":"","orcid":"","institution":"McGill University Health Centre","correspondingAuthor":false,"prefix":"","firstName":"Mathieu","middleName":"","lastName":"Boily","suffix":""},{"id":597148031,"identity":"34556d8f-40e8-4b81-a2e6-6e086f180d09","order_by":4,"name":"Michael Chetrit","email":"","orcid":"","institution":"McGill University Health Centre","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Chetrit","suffix":""}],"badges":[],"createdAt":"2026-02-07 23:38:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8818347/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8818347/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103733240,"identity":"ba3237b8-793d-4e01-bf24-52dd6e87a93f","added_by":"auto","created_at":"2026-03-02 09:27:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":568851,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnnotated Axial and Coronal T1-Weighted Wrist MRI Showing Carpal Tunnel and Anatomical Structures. \u003c/strong\u003eThe axial view highlights the location of each anatomical structure within the carpal tunnel at the hook of the hamate, with the following color coding: carpal bones (orange), flexor digitorum profundus (FDP) tendon (green), flexor digitorum superficialis (FDS) tendon (yellow), flexor pollicis longus (FPL) tendon (teal), median nerve (pink), and flexor retinaculum (red). The extensor carpi ulnaris (ECU) tendon (light blue) is noted outside the carpal tunnel. The coronal view provides an additional perspective, showing wrist anatomy with a red line indicating the location of the hook of the hamate.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8818347/v1/3f798fcedd95bd8f54e2d13a.png"},{"id":103733188,"identity":"a00dafe6-66cb-4c76-afce-ed6bffaefb66","added_by":"auto","created_at":"2026-03-02 09:27:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1234646,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProton Density–Weighted Wrist MRI in ATTRwt and Amyloid-Negative Subjects. \u003c/strong\u003eProton density-weighted axial images highlighting distinct features in tendon thickening, tenosynovium signal intensity, and carpal tunnel morphology between ATTR amyloidosis (A) and an Amyloid Negative Control (B).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8818347/v1/54f398380cb6185eb6ecbcf6.png"},{"id":103733274,"identity":"f672c48e-fae3-4a20-beaa-e99122c0344a","added_by":"auto","created_at":"2026-03-02 09:27:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":315338,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMagnetization Transfer Ratio (MTR) Imaging of the Wrist in ATTR. \u003c/strong\u003eAxial MTR map of the wrist demonstrating elevated ratios in the tenosynovium, flexor tendons, and median nerve in the ATTR subject (Amyloid +) compared to the amyloid negative (Amyloid -) control. Increased color intensity (blue to red) reflects higher MTR values, indicating greater macromolecular density.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8818347/v1/5a63b65cb557be1e258705b9.png"},{"id":103733495,"identity":"0926b0b0-b910-426d-af6d-4024a745e8af","added_by":"auto","created_at":"2026-03-02 09:28:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2816968,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8818347/v1/ec3ab82e-b0d7-431e-93f4-c132eb4eb5fb.pdf"},{"id":103733245,"identity":"abc4228c-f4bf-4834-907e-c45c2d90bc4e","added_by":"auto","created_at":"2026-03-02 09:27:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":575911,"visible":true,"origin":"","legend":"","description":"","filename":"CAREChecklistEnglish2013.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8818347/v1/069546c4dabede66b3a22de0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"MRI Features in Transthyretin Amyloidosis of the Carpal Tunnel and Amyloid-Negative Control: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAmyloidosis is a systemic disorder characterized by extracellular deposition of misfolded proteins as insoluble fibrils in various tissues [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Among its subtypes, transthyretin amyloidosis (ATTR) is a particular case stemming from the misfolding of transthyretin, a transport protein primarily synthesized in the liver, with a prevalence of 16.6 cases per million people [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These insoluble amyloid fibrils progressively infiltrate organ systems and connective tissues, leading to structural disruption and loss of function. Two major subtypes are recognized: hereditary ATTR, which stems from mutations in the TTR gene, and wild-type ATTR (ATTRwt), which is associated with aging [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Furthermore, ATTRwt is increasingly recognized as a common cause of heart failure in older adults [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], but early extra-cardiac manifestations, particularly within the musculoskeletal system, are frequently underappreciated [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCarpal tunnel syndrome (CTS) is one of the earliest and most prevalent peripheral manifestations of ATTR amyloidosis, with studies estimating that approximately 10\u0026ndash;15% of patients with CTS have underlying amyloid deposition [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. CTS arises from compression of the median nerve within the carpal tunnel and typically presents with pain, numbness, and hand weakness. In the setting of ATTR, amyloid deposits accumulate in the flexor tendons, transverse carpal ligament, and surrounding tenosynovium, leading to tissue hypertrophy and progressive nerve entrapment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIndeed, CTS often precedes the diagnosis of systemic ATTR by 4 to 10 years and may serve as an indicator for both ATTRwt and ATTRv [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recognition of this relationship is critical, as bilateral CTS in older patients may reflect underlying systemic amyloidosis.\u003c/p\u003e \u003cp\u003eWhile histopathological confirmation through biopsy remains the diagnostic reference standard, it is only performed in patients with severe carpal tunnel syndrome and willing to undergo release surgery. Imaging may play an important role in the non-invasive assessment of amyloid-related CTS. Conventional MRI can detect morphological abnormalities such as tendon thickening and nerve enlargement but lacks specificity for amyloid infiltration. These MRI findings may allow clinicians to identify patients who warrant further diagnostic evaluation using histopathological testing, facilitating diagnosis before cardiac or other organ involvement becomes clinically apparent.\u003c/p\u003e \u003cp\u003eIn this report, we describe the MRI findings in a 65-year-old male with biopsy-confirmed wild-type ATTR and bilateral CTS. This case shows distinct imaging features of amyloid involvement in the carpal tunnel, including striated hyperintensity within the thickened tenosynovium and flexor tendons. Few studies to date have detailed amyloid-associated alterations in the wrist. As such, this case highlights the diagnostic potential of MRI in identifying early peripheral amyloid involvement and may guide future research aimed at integrating musculoskeletal imaging into the diagnostic pathway for systemic amyloidosis.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 65-year-old male first presented to the clinic for cardiac evaluation. His past medical history included a remote episode of pericarditis in 2009, without clinical signs of congestive heart failure. Subsequent investigations led to a diagnosis of ATTRwt. At the time of cardiac evaluation, the patient reported persistent mild numbness in the right wrist. He had a history of severe bilateral CTS, more pronounced on the right, characterized by chronic numbness, pain, and sharp tingling sensations. He had previously undergone bilateral carpal tunnel release surgery and histopathological analysis of tenosynovial tissue obtained during the procedure revealed amyloid deposition, which retrospectively confirmed the diagnosis of ATTRwt in 2022. No pre-operative MRI of the wrists was performed prior to the carpal tunnel release procedures.\u003c/p\u003e\n\u003cp\u003eWrist MRI was performed on April 12, 2024, to further investigate persistent CTS-related symptoms. At the time of evaluation, no pharmacological treatment targeting ATTRwt had been initiated. The protocol included T1-weighted and proton density sequences. Following MRI comparison with a 76 year old amyloid negative patient with moderate-severe CTS, imaging revealed multiple findings consistent with amyloid deposition. There was marked thickening of the flexor tendons bilaterally, with abnormal signal intensity qualified as striated and heterogeneous infiltration. The tenosynovium appeared hyperintense with internal striations and diffuse thickening. The carpal tunnel itself exhibited a cloudy appearance suggestive of fluid accumulation, potentially representing edema. The median nerve was severely compressed, with visible enlargement, nodular thickening, and disrupted fascicular architecture. Moderate-to-severe thickening of the flexor retinaculum was also observed (Fig. 2).\u003c/p\u003e\n\u003cp\u003eFurther quantitative analysis demonstrated that the ATTR subject exhibited overall larger tissue structures compared with the amyloid-negative subject (Table 1).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQuantitative Features\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eATTRwt\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAmyloid Negative\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSA of Carpal Tunnel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 2.81 | Left: 2.62\u003c/p\u003e\n \u003cp\u003eAverage: 2.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 1.7 | Left: 1.71\u003c/p\u003e\n \u003cp\u003eAverage: 1.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNerve Diameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.36 | Left: 0.20\u003c/p\u003e\n \u003cp\u003eAverage: 0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.20 | Left: 0.14\u003c/p\u003e\n \u003cp\u003eAverage: 0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetinaculum Thickness (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.21 | Left: 0.23\u003c/p\u003e\n \u003cp\u003eAverage: 0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.16 | Left: 0.13\u003c/p\u003e\n \u003cp\u003eAverage: 0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSA of All Tendons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 1.26 | Left: 1.19\u003c/p\u003e\n \u003cp\u003eAverage: 1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.96 | Left: 0.96\u003c/p\u003e\n \u003cp\u003eAverage: 0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSA of FDP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.69 | Left: 0.66\u003c/p\u003e\n \u003cp\u003eAverage: 0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.44 | Left: 0.42\u003c/p\u003e\n \u003cp\u003eAverage: 0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSA of FDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.47 | Left: 0.42\u003c/p\u003e\n \u003cp\u003eAverage: 0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.32 | Left: 0.32\u003c/p\u003e\n \u003cp\u003eAverage: 0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSA of FPL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.10 | Left: 0.11\u003c/p\u003e\n \u003cp\u003eAverage: 0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.20 | Left: 0.22\u003c/p\u003e\n \u003cp\u003eAverage: 0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSA of ECU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.40 | Left: 0.39\u003c/p\u003e\n \u003cp\u003eAverage: 0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.14 | Left: 0.16\u003c/p\u003e\n \u003cp\u003eAverage: 0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThird Space Thickness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 1.19 | Left: 1.23\u003c/p\u003e\n \u003cp\u003eAverage: 1.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRight: 0.54 | Left: 0.61\u003c/p\u003e\n \u003cp\u003eAverage: 0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eQuantitative morphometric analysis of wrist structures demonstrating differences in carpal tunnel cross-sectional area, median nerve diameter, and flexor tendon bulk between the right and left sides of ATTRwt and amyloid negative subjects. Measurements included the median nerve, individual flexor tendons, the ECU, and third space thickness. Note: All values in cm² unless otherwise specified. CSA: Cross-sectional area; MN: Median nerve; FDP: Flexor digitorum profundus; FDS: Flexor digitorum superficialis; FPL: Flexor pollicis longus; ECU: Extensor carpi ulnaris; TSVM: Tenosynovium. Values represent the average of each patient's right and left wrists.\u003c/p\u003e\n\u003cdiv\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1. Quantitative Morphometric Analysis of Wrist Structures in ATTRwt compared with an Amyloid-Negative Control.\u0026nbsp;\u003c/strong\u003eCross-sectional areas (CSA), nerve diameter, and other structural measurements in ATTRwt compared with an Amyloid-Negative Control.\u003c/p\u003e\n \u003cp\u003eMoreover, severe tendinosis of the extensor carpi ulnaris and mild-to-moderate erosive changes of the carpal bones were observed in the ATTR subject, compared with only mild findings in the amyloid-negative subject (Table 2).\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQualitative Features\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eATTRwt\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAmyloid Negative\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTenosynovium Thickness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetinaculum Thickness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModerate-to-Severe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECU Tendinosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild-to-Moderate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCarpal Bone Erosion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild-to-Moderate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eNote: ECU: Extensor carpi ulnaris; MTR: Magnetization Transfer Ratio; Severe: Marked structural or pathological changes that are clearly abnormal and likely to impact function; Moderate: Noticeable alterations that may contribute to dysfunction but are not as severe or widespread; Mild: Minimal changes that are present but unlikely to have a significant functional impact.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;2. Qualitative MRI Features of the Wrist in ATTRwt and an Amyloid-Negative Control.\u003c/strong\u003e Subjective grading of tenosynovium thickness, retinaculum thickness, tendinosis, and bone erosion in ATTRwt and an amyloid negative control.\u003c/p\u003e\n\u003cp\u003eCorresponding magnetization transfer ratio (MTR) imaging confirmed these findings, demonstrating globally elevated ratios within the tenosynovium, flexor tendons, and median nerve compared with the amyloid-negative subject (Fig. 3).\u003c/p\u003e\n\u003cp\u003eThese elevations, consistent with the T1 and PD observations, suggest increased macromolecular density in the affected tissues.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case supports a growing body of evidence suggesting that MRI can serve as a valuable noninvasive tool in the assessment of amyloid-related CTS. While CTS is a common condition in the general population, its association with ATTR, is increasingly recognized as a potential early clinical manifestation. In this patient, detailed wrist MRI revealed characteristic features of amyloid infiltration, including thickened flexor tendons with striated signal changes, hyperintense tenosynovium, and severe median nerve compression, findings that align with previously reported imaging patterns of amyloid deposition. These observations underscore the utility of MRI not only for symptom evaluation but also for identifying musculoskeletal involvement in systemic amyloidosis, potentially aiding in earlier diagnosis.\u003c/p\u003e \u003cp\u003eWhile there are publications describing MRI findings in amyloidosis, there is currently no published literature describing MRI evaluation of specifically ATTR amyloidosis in the wrist. A study describing β2-microglobulin amyloid deposition in the wrist [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] demonstrates imaging findings with similarities to those observed in this case. However, this area remains significantly under-researched. This gap in the literature further strengthens the rationale for the present case study, which aims to demonstrate the potential role of MRI as a non-invasive tool to promote further investigation of ATTR amyloidosis.to promote further investigation of ATTR amyloidosis.\u003c/p\u003e \u003cp\u003eWhile tenosynovial biopsy remains the reference standard for confirming amyloid deposition, it is typically reserved for more severe cases and performed at the surgeon\u0026rsquo;s discretion. As a result, many patients with mild to moderate symptoms of CTS may not undergo tissue sampling or any MRI imaging, leading to missed opportunities for early diagnosis of systemic amyloidosis. In carpal tunnel patients with clinical suspicion or risk factors for amyloidosis, non-invasive wrist MRI may offer an opportunity to identify imaging features suggestive of amyloid involvement, thereby prompting targeted referral for further amyloid-specific evaluation without immediate need for invasive testing. In carpal tunnel patients with clinical suspicion or risk factors for amyloidosis, non-invasive wrist MRI may offer an opportunity to identify imaging features suggestive of amyloid involvement, thereby prompting targeted referral for further amyloid-specific evaluation without immediate need for invasive testing. Importantly, the distinct MRI findings observed in this case highlight the potential role of imaging in recognizing amyloid involvement in patients presenting with CTS who have not yet been evaluated for systemic disease. These underutilized radiologic markers, such as striated tendon signal changes, tenosynovial thickening, and nerve compression and fascicular distortion, may serve as early indicators of transthyretin amyloidosis, even in the absence of overt cardiac symptoms. In clinical practice, MRI could support decision-making around whether to pursue biopsy during carpal tunnel release surgery, helping to identify amyloid earlier and guide appropriate referral for systemic evaluation.\u003c/p\u003e \u003cp\u003eFor qualitative assessment, a three-tier severity grading system was applied based on expert radiologic interpretation of tissue thickening and structural alteration (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eThis grading scale categorizes findings as severe, reflecting marked structural or pathological changes likely to impact function; moderate, indicating noticeable alterations that may contribute to dysfunction but are not extensive; and mild, representing minimal changes unlikely to have significant functional impact. This framework was used to standardize descriptive interpretation of imaging findings in the absence of established quantitative thresholds and serves as an exploratory approach pending future validation.\u003c/p\u003e \u003cp\u003eGiven the availability of disease-modifying therapies for ATTRwt, early identification is essential to improving patient outcomes. Although this report is limited to a single case, it highlights an imaging phenotype that warrants further investigation to determine whether specific MRI patterns can reliably suggest the presence of ATTRwt. While standard MRI can detect features such as tendon thickening, tenosynovial changes, and median nerve enlargement which may be found in other systemic disorders, the extent of thickening in addition to the integration of advanced techniques, such as MTR imaging and T1rho mapping may enhance the ability to quantify amyloid burden and differentiate ATTR-related changes from more common causes of CTS. MTR imaging assesses macromolecular content within tissue; in the context of amyloidosis, elevated MTR values may reflect increased amyloid fibril deposition, offering a noninvasive surrogate marker of disease burden [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Comparative and quantitative imaging approaches may help refine diagnostic criteria, offering noninvasive alternatives to tissue biopsy. T1rho mapping could help assess cartilage integrity, aiding in the understanding of amyloid infiltration processes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These technical refinements not only improve diagnostic confidence but also hold promise for future use in monitoring disease progression and therapeutic response; further investigation is currently underway to better define their clinical applicability.\u003c/p\u003e \u003cp\u003eIn summary, this case demonstrates the potential of MRI to detect musculoskeletal involvement in ATTRwt amyloidosis and underscores its role in identifying amyloid-related CTS. These findings support the need for further research into integrating advanced musculoskeletal MRI into the diagnostic algorithm for transthyretin amyloidosis, highlighting its potential role in early detection prior to overt cardiac involvement and in guiding clinical decision-making.\u003c/p\u003e\n\u003ch3\u003ePatient Perspective\u003c/h3\u003e\n\u003cp\u003eThe patient reflected that receiving the diagnosis of systemic amyloidosis was a difficult experience for both himself and his family. Learning of the condition at 65 years of age added to the emotional weight of the diagnosis. The carpal tunnel release surgery provided meaningful symptomatic relief; however, he mentioned the improvement was temporary, as loss of mobility and intermittent pain persisted due to the severity of amyloid already present. Still, he expressed appreciation for the MRI evaluation and this study, noting that it offered a clear window into what was truly occurring within his wrists. Additionally, the imaging findings were reviewed with radiologists and physicians, who indicated that this level of detailed characterization in the early stages of disease may help enable monitoring in patients who are often undetected, particularly those with mild to moderate carpal tunnel symptoms.\u003c/p\u003e \u003cp\u003eHe also shared that learning about this research brought him comfort, knowing that a non-invasive early detection method could help others like him whose lives are fundamentally changed by the disease. He emphasized that identifying amyloidosis earlier could enable treatments to alter the disease course, and that this possibility gave him genuine hope for future patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch4\u003eAuthor Contribution:\u003c/h4\u003e\n\u003cp\u003eAll authors were involved in the case and preparation of the manuscript and/or imaging.\u003c/p\u003e\u003cp\u003eEthics approval: The protocol was approved by McGill University Health Center Research Ethics Board - Centre for Applied Ethics in accordance with the International Council for Harmonisation Guideline E6 (Revision 3) on Good Clinical Practice and the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2022).\u003c/p\u003e\n\u003cp\u003eConsent to Participate: Informed consent was obtained from the patient for participation in this study.\u003c/p\u003e\n\u003cp\u003eConsent to Publish: Informed consent was obtained from the patient for publication.\u003c/p\u003e\n\u003cp\u003eConflict of interest: The authors declare no conflict of interests.\u003c/p\u003e\n\u003cp\u003eData Availability:\u003c/p\u003e\n\u003cp\u003eQualitative MRI features of the wrist are documented in Table 2. This dataset includes descriptive features observed in MRI scans, offering insights into the qualitative aspects of wrist imaging.\u003c/p\u003e\n\u003cp\u003eQuantitative morphometric analysis of wrist structures is available in Table 1. This dataset provides detailed measurements and analysis of various wrist structures, contributing to the understanding of wrist morphology.\u003c/p\u003e\n\u003cp\u003eThe data that supports the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\u003ch4\u003eAcknowledgments\u003c/h4\u003e\n\u003cp\u003eJean-Pierre Abdallah served as the primary author of the manuscript. Marcus Saldanha contributed as a co-author, was responsible for patient recruitment, performed the MRI scans, and provided assistance in manuscript preparation.\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledge the support of the McGill University Health Centre, particularly the Department of Radiology, and Dr. Mathieu Boily (MSK Radiologist) for his guidance. We also thank the Courtois Cardiovascular Signature Program and the Courtois CMR Research Group for access to the GE MRI system, as well as MRI technologist Maggie Leo for her expertise and assistance with image acquisition.\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the patient who participated in this study for their time and cooperation. The authors are also grateful to Dr. Michael Chetrit, Dr. Mathieu Boily, and Dr. Javad Raffee for their valuable input and support throughout the course of this project.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAsh S, Shorer E, Ramgobin D, Vo M, Gibbons J, Golamari R, et al. Cardiac amyloidosis - A review of current literature for the practicing physician. Clin Cardiol. 2021;44(3):322\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/clc.23572\u003c/span\u003e\u003cspan address=\"10.1002/clc.23572\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. 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J Am Coll Cardiol. 2018;71(25):2919\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jacc.2018.03.536\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2018.03.536\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Amyloidosis, Carpal Tunnel Syndrome, Transthyretin Amyloid, Magnetic Resonance Imaging, Magnetization Transfer Ratio","lastPublishedDoi":"10.21203/rs.3.rs-8818347/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8818347/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAmyloidosis is a systemic disorder characterized by extracellular protein deposition, with transthyretin amyloidosis being the most common subtype. Carpal tunnel syndrome is a frequent early manifestation, yet detailed MRI characterization of amyloid deposition in the wrist remains limited.\u003c/p\u003e \u003cp\u003eWe present MRI findings from one severe transthyretin amyloidosis case: a 65-year-old male with severe carpal tunnel syndrome secondary to transthyretin amyloidosis wild-type. The subject underwent wrist MRI using T1 and proton density sequences. This case demonstrated extensive flexor tendon thickening, severe tenosynovitis, and hyperintense, striated amyloid deposition within the tenosynovium.\u003c/p\u003e \u003cp\u003eMRI revealed distinct patterns of amyloid involvement in carpal tunnel syndrome, highlighting potential imaging biomarkers for characterizing transthyretin amyloidosis and enabling the early detection of cardiac involvement. These findings highlight the potential of MRIs in non-invasive amyloid characterization. As such, larger studies would be required to further validate these observations and integrate MRI into early amyloidosis diagnostic pathways.\u003c/p\u003e","manuscriptTitle":"MRI Features in Transthyretin Amyloidosis of the Carpal Tunnel and Amyloid-Negative Control: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-02 09:23:43","doi":"10.21203/rs.3.rs-8818347/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-13T12:09:30+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T21:43:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66394589740283329458610024742676637637","date":"2026-03-22T10:05:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"63147423174640886062274121985412783170","date":"2026-03-16T06:36:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-09T08:19:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"260123233116581834051925059858574447408","date":"2026-02-27T11:00:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-25T10:39:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-18T11:37:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-17T13:48:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Medicine","date":"2026-02-17T13:44:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"98ab3ae0-4682-49cd-a4b4-506fd5d7e081","owner":[],"postedDate":"March 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-05T09:23:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-02 09:23:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8818347","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8818347","identity":"rs-8818347","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}